CVS 6 - Haemostasis Flashcards
Causes of thrombosis
• Endothelial Injury
– Major cause of thrombus occurring in heart/arteries
– Sheer stress (hypertension), hyperlipidemia, other vascular injury (eg smoking)
• Abnormal blood flow
– Replace laminar flow with
» Turbulent flow (plaques, arrhythmia ) damages endothelium
» Stasis major cause of thrombus in vein – active co-agulation factors “pool”
• Hypercoagulability
– Genetic (eg in Factor V)
– Acquired (eg herparin induced, eg estrogens increase synthesis of coagulation factors)
Virchow’s triad
3 factors affect one another to induce thrombosis
- Endothelial injury
- Abnormal blood flow
- Hypercoagulability
Arterial and venous thrombosis are different
Arterial thrombosis
- More platelet rich
- Outcome: Stroke, heart attack
- Risk factors –vascular disease: smoking, diabetes, b.p., weight, cholesterol
- Treatment: Reduce risk factors, Anti-platelet drugs
Venous thrombosis
- More fibrin rich
- Outcome: DVT, Pulmonary embolism
- Risk factors: genetic predisposition slow blood flow
- Treatment: Prophylactic treatment with anti- coagulants
Haemostasis: clinical applications
• Anti-platelet drugs
– Inappropriate platelet aggregation
» Due to endothelial injury, abnormal blood flow, hypercoagulability
– Examples of application
» prevention of stroke
» Prevention of MI in stable angina, unstable angina or peripheral vascular disease
» after M.I.
» during bypass surgery, haemodialysis
– much less/not effective against venous thrombosis !
• Anti-coagulants
– deep vein thrombosis leading to pulmonary embolism
» high risk of DVT in persons over 40 admitted to hospital for major surgery
– thrombosis triggered by prosthetic heart valves
– atrial fibrillation increases risk of arterial thromboembolism
• Fibrinolytic agents – acute MI
– pulmonary embolism
Anti-platelet drugs (1): aspirin
• Mechanism
– inhibits COX1 by acetylation, inhibits prostaglandin synthesis in platelets
– platelets are anucleate (no nucleus to encode mRNA)-> irreversible
» low infrequent dose suffices (little analgesia) 75 mg to inhibit platelets, but
300mg for suspect MI
– minimal ADR at low dose and simple dosing often treatment of choice
• Indications
– primary and secondary prevention of thromboembolism in artherosclerotic disease: angina, MI, stroke, peripheral vascular disease
– analgesia; anti inflammatory for rheumatoid arthritis
• PK
Acetyl salicylic acid -> (liver) Salicylate -> glucoronide conjugate -> (kidney) urine
t1⁄215 min
600 mg: t1⁄2 3 hours
>600 mg: t1⁄2 9 hours “Non-linear pharmacokinetics”
t 1/2 of platelets
7 days
Anti-platelet drugs (1): aspirin - ADR, caution, contraindication and interaction
• ADR
– 6 serious haemorrhages per 1000 patients per year !
– hypersensitivity - rash
• Cautions & contraindications
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
– can cause and worsen asthma
– avoid in renal insufficiency
– hypertension increases risk of bleeding
• Drug interactions
– care when used with anticoagulants and other anti-platelet drugs
– can be antagonised by other NSAIDS!
– can antagonise effect of diuretics
Interaction between NSAID and aspirin
NSAIDS compete with aspirin, reducing its ability to acetylate COX1
Anti-platelet drugs (2): PDE inhibitor
Dipyridamole
• Mechanism
– cAMP Phosphodiesterase inhibitor - promotes activation of PKA which inhibits platelet activation
– also inhibits reuptake of adenosine into platelets
• Indications
– weak anti-platelet drug – not often used on own
– in prevention of embolism from prosthetic heart valve (combination with warfarin)
– prevents vessel block in patients with ischaemic stroke (combination with low dose aspirin)
• ADR
– bleeding – but less common than with other anti-platelet drugs
– headache, diarrhoea
– facial flushing (from vasodilation)
• Cautions
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
• Drug- interactions
– may cause haemorrhage in patients taking anticoagulants
Don’t get confused with role of cAMP in cardiac tissue
- In cardiac myocytes, cAMP (protein kinase A) promotes contractility •In Vascular smooth muscle cAMP promotes relaxation and hence vasodilation
- In platelets cAMP inhibits aggregation
Anti-platelet drugs (3): ADP receptor (P2Y) antagonists 2nd gen
Clopidogrel (2nd gen)
• Mechanism
– ADP receptor antagonist
(efficacy reduced by P450 inhibitor)
– pro-drug activated by p450 2C19 metabolism potential for drug-drug interaction
– active metabolite binds irreversibly to receptor
• PK
– 300 mg loading dose helpful to speed up platelet inhibition then 75 mg p.o.
– excreted in urine
• Indications
– acute coronary syndromes
– secondary prevention of artherosclerosis in angina, after MI, stroke, peripheral vascular disease
– useful in patients intolerant of aspirin
• ADR
– Haemorrhage – made problematic by irreversibility
– abdominal pain, nausea
• Cautions
– avoid in patients at high risk of serious bleeding (eg peptic ulcer, hypertension, hepatic & renal insufficiency, haemophilia, pregnancy (intrauterine bleeding risk)
• Contraindications
– active bleeding and breast feeding
• Drug interactions
– increases risk of bleeding if used with aspirin, other anti-platelet drugs, warfarin
Anti-platelet drugs (3): ADP receptor (P2Y) antagonists 1st + 3rd gen
Ticlopidine (1st generation)
• causes neutropenia, thrombocytopenia – need monitor blood cell counts so used less frequently
Pasugrel (3rd generation)
• Also pro-drug, rapidly activated by P450
• Also irreversible
Anti-platelet drugs (4): GPIIb/IIIa antagonists
• Mechanism
• Mechanism – GPIIbIIIa antagonists – very effective because inhibit “end-point” of platelet aggregation” • Drugs – Eptifibatide » peptide antagonist – Abciximab » chimaeric mouse human mAb (Fc is human, Fab is murine) » i.v. bolus then continuous infusion » dissociates very slowly from receptor (dissoc t1⁄2~ 24 h) long lasting blockade, need platelet infusion to reverse – Tirofiban » reversible inhibitor • Indications – only used under specialist supervision – unstable angina • ADR – all can cause bleeding. • Caution – avoid in patients at high risk or if active bleeding - could be catastrophic – long list! Check these! • Contraindications – recent abnormal bleeding or stroke
Anti-coagulants:Heparin (1)
• Mechanism
– sulphated polysaccharide extracted from bovine lung or porcine intestine
– inhibit Factors IX, Xa, XIa, XIIa and thrombin by catalysing irreversible binding of anti-thombin III
• Drugs
– Unfractionated heparin: 3-30 kD
» Poor Foral i.v. admin and short t1/2< 1 h
– low molecular weight heparin (LMWH) – fraction < 7 kD
» enoxaprin, dalteparin, tinzaparin - more commonly used than unfractionated heparin
» longer t1/2
» good absorption by s.c. injection
• Indications
– full dose – when rapid anticoagulation needed, eg acute coronary syndromes, thromboembolic disease
– lower dose –prophylactic treatment
• PK
– only given parenterally, so short term use only
• ADR
– low therapeutic index – monitoring usual with unfractionated heparin because effects less predictable. Monitoring not required for LMWH
– haemorrhage (esp. in elderly)
– thrombocytopenia (heparin induced anti-platelet antibodies causing platelet aggregation!). Risk lower with LMWH
• Cautions
– Risk/benefit should always be considered
– factors to consider include:
» age (elderly at greater risk of bleeding)
» recent trauma/surgery
» peptic ulcer
» severe hypertension
» pregnancy
» severe renal insufficiency (greater risk of bleeding)
• Contra-indications
» haemophilia, thrombocytopenia (see ADR!), severe hepatic disease
• Drug interactions
– care if used with drugs that increase likelihood of bleeding eg NSAIDS
Anti-coagulants : warfarin (1)
• Mechanism of action
– Inhibition of vitamin K synthesis & synthesis of clotting factors.
– “Delayed effect” – it takes a few days for pre-existing vitamin K and clotting factors to be turned over. Use other treatment for rapid effect
– few days to reverse drug effect on stopping.
• Indications
– when long-term anti-coagulation required eg prophylatic treatment of thromboembolic disease
• PK
– Foral high – p.o. admin
– long t1/2 ~ 1 day
• ADR
Haemorrhage, Low therapeutic window
• Caution
Need for monitoring – I.N.R.
– assess risk benefit
• Contraindications
– teratogenic – avoid during pregnancy
– peptic ulcer
• Drug interactions –need serious consideration!:
– 99% plasma protein bound - other drugs may displace (eg NSAIDS) →↑ [drug]free
– antibiotics (bacteria can produce vitamin K – bypass warfarin)
– cyt P450 metabolism esp 2C9
» drugs that inhibit p450 →↑ [drug] (eg amiodarone, cimetidine, clopidogrel, fluconazole, fluoexetine…..)
» drugs that induce P450 (eg barbiturates, carbamezapine, phenytoin, alcohol)→↑ elimination
